Abstract ? Project I The overarching goal of the Prometheus consortium is to develop antibody-based prophylactics and therapeutics against three major groups of Category A priority viruses that pose the highest risk to national security and public health and cause zoonotic disease?ebolaviruses, the nairovirus Crimean-Congo hemorrhagic fever virus (CCHFV), the New-World hantaviruses Andes virus (ANDV) and Sin Nombre virus (SNV), and the Old-World hantavirus Puumula virus (PUUV). No approved treatments are available for any of these viruses. Given the safety and efficacy of over 50 mAb-based therapies currently available in market for various diseases, mAbs are a low-risk platform to develop countermeasures for these Category A viruses. The rapid discovery and development of large numbers of pathogen-specific human monoclonal antibodies (mAbs) from convalescent and acutely infected donors is the central strength to our platform. Coming from hosts who have already mounted an effective antibody response, these naturally occurring mAbs are less likely to elicit tissue cross-reactivity and in vivo toxicity in humans and also obviate the need for chimerization or time- consuming humanization. Prometheus will use these mAbs as raw material to produce broadly protective immunotherapeutics that (i) are robust to natural viral genotypic variation; (ii) leverage multi-epitope targeting and an innovative feature we term RAVE (reciprocal antagonism to viral escape) to enhance potency and resist escape of viral neutralization; (iii) exploit tuned Fc effector properties for extended in vivo half-life and more effective elimination of viral particles and infected cells; and (iv) can be directly and rapidly transitioned to advanced pre-clinical development. Project I will work collaboratively with Project II to identify human mAbs and oligoclonal mAb cocktails against CCHFV and hantaviruses (SNV, ANDV, and PUUV) with these properties?pan-ebolavirus lead human mAbs have already been identified by Prometheus members. We will hand off lead mAbs and cocktails to Core B as candidates for advanced development of therapeutics, and to Project III for studies aimed at the generation of DNA-encoded mAbs (DMAbs) for prophylactic delivery. In consultation with the SAC, lead molecules will be evaluated by Core C for protective efficacy in NHP models of CCHFV and SNV challenge.